Molecular Structure and Function of Crystallins

在人和动物模型中，γ-晶体蛋白与白内障有关。gS-晶状体蛋白是成人透镜中主要的bg-晶状体蛋白，并且还发现在黄斑变性模型的视网膜色素上皮中被诱导。在小鼠中，gS基因已被切除，导致正常纤维细胞成熟的破坏。酵母双杂交实验，以确定相互作用的合作伙伴的gS正在进行中。小鼠gS-晶状体蛋白的NMR结构分析显示了柔性接头和N-末端区域在提供蛋白质溶解度的熵贡献中的重要作用。我们还发现，突变蛋白质在Opj透镜中形成淀粉样斑块。与小鼠Opj白内障相关的突变型gS的结构正在确定中，并且正在揭示蛋白质解折叠的过程。这对其他蛋白质折叠疾病如淀粉样蛋白疾病也有影响。 g-和β-晶体蛋白的结构和稳定性取决于高度保守的氨基酸残基的模式。这种序列特征也存在于晶状体蛋白的非晶状体亲属中，例如在黑素瘤1（AIM 1）中不存在，黑素瘤1是控制黑素瘤中恶性肿瘤的蛋白质暗示。然而，像AIM 1这样的蛋白质对稳定性的要求比晶体蛋白低，可能会损害结构稳定性，以发挥额外的功能作用。在合作研究中，我们研究了人类AIM 1最不同结构域的结构。X射线分析表明，基本结构是保守的，而关键残基的丢失使部分结构松动。

gamma-crystallins are associated with cataract in both human and animal models. gS-crystallin is the major bg-crystallin in the adult human lens and has also been found to be induced in retinal pigment epithelium in models of macular degeneration. The gene for gS has been ablated in mouse, leading to disruption of normal fiber cell maturation. Yeast 2-hybrid experiments to determine interaction partners for gS are in progress. NMR structure analysis of mouse gS-crystallin has shown important roles for flexible linker and N-terminal regions in providing entropic contributions to protein solubility. We have also shown that the mutant protein forms amyloid-like plaques in the Opj lens. The structure of mutant gS associated with the mouse Opj cataract is now being determined and is shedding light on the processes of protein unfolding. This has implications for other protein folding diseases such as amyloid diseases. The structure and stability of g- and beta-crystallins are dependent on a pattern of highly conserved amino acid residues. This sequence signature is also present in non-lens relatives of the crystallins, such as absent in melanoma 1 (AIM1)a protein implication in control of malignancy in melanoma. However proteins like AIM1 which have a lower requirement for stability than crystallins may compromise structural stability for additional functional roles. In collaborative studies we have investigated the structure of the most divergent domain of human AIM1. X-ray analysis shows that the basic structure is conserved, while loss of key residues has loosened parts of the structure.